1. POMH-UK Topic 1
Prescribing of high-dose and combination antipsychotics for patients on adult acute and psychiatric intensive care wards
Supplementary audit 1d
© 2009 The Royal College of Psychiatrists. For further information contact

2. Combined antipsychotics
Consistent recommendations for monotherapy with antipsychotic drugs (Lehman & Steinwachs 1998, NICE guideline 2002)
Literature review
40% of schizophrenic patients receiving antipsychotic combination (Cannales et al 1999, Taylor et al 2000)
POMH-UK baseline audit (Jan 2006)
32 Trusts
218 acute adult and PICU wards
3492 patients
36% prescribed high dose
42% prescribed combined antipsychotics
The evidence base underpinning the efficacy of antipsychotic drugs is derived, in the main, from randomised controlled trials (RCTs) that assess the use of these drugs as monotherapy. RCTs are the ‘gold standard’ method of assessing the efficacy and tolerability of treatment interventions. These studies are very expensive to conduct and the majority of large RCTs are fully funded by the pharmaceutical industry.
RCTs that examine the efficacy and tolerability of antipsychotic combinations (with the exception of a small number of studies involving clozapine) have not been conducted. There is therefore no higher level evidence that such combinations are effective or safe. Note in this context that no evidence of benefit is not the same as evidence of no benefit.
Despite the clear recommendations contained in treatment guidelines, the use of combinations of antipsychotic drugs is common across the world and has been relatively consistent over time. The findings of the POMH-UK baseline audit illustrate the magnitude of the difference between guideline recommendations and clinical practice.
Patients who are prescribed combined antipsychotics are at greater risk of receiving a high dose, eg 2 antipsychotics, each of which is prescribed at 75% of its maximum dose results in the patient being prescribed 150% (a high dose). There is no evidence that high doses of antipsychotics are more effective than standard doses.

3. Potential reasons for combined antipsychotics
Cross-titration (active or aborted)
Poor communication between services
Patient’s/family’s choice
Enhance therapeutic effect
Speed-up effect
Different target symptom
Different symptom domain
Reduce adverse effects
Different route of administration
This slide covers potential reasons that clinicians may have for prescribing combined antipsychotics.
For example the treatment plan may be to switch the patient from one antipsychotic to another by titrating down the dose of the ‘old’ antipsychotic while titrating up the dose of the ‘new’ one. If the patient shows clinically meaningful improvement midway through this process, the plan to stop the ‘old’ drug may be abandoned.
Some prescribers may be trying to speed up the onset of effect in a patient who is very unwell or may be trying to achieve positive change in specific target symptoms (such as negative symptoms) or specific behaviours (such as aggression to others). In the POMH-UK baseline audit, the reason given by clinicians for 45% of prescriptions for combined antipsychotics was for the control of disturbed behaviour.

4. Potential concerns Risks Higher than necessary total dosage
Increased side effects (acute or long-term)
Drug-drug interactions
? increased mortality
Increased cost
Uncertainties
Increased risk of non-adherence
Difficulty determining cause and effect
Lack of evidence
There are a number of concerns relating to the use of combined antipsychotics.
Remember at this point that combined antipsychotics (with the exception of a small number of studies involving clozapine) have not been subject to RCTs.
There is no evidence that combined antipsychotics not including clozapine are more effective than a single antipsychotic and some evidence to support combined antipsychotics being associated with an increased side effect burden.
One of the concerns is the potential for antipsychotics to cause QTc prolongation and the associated risk of cardiac arrhythmias. The MHRA have reviewed the cardiovascular safety of all antipsychotics available in the UK, and have recommended that the wording ‘avoid concomitant neuroleptics’ should be added to the special warnings and precautions for use section of the SPC for every antipsychotic.
See the clinical introduction in the baseline Topic 1 report for a fuller explanation of the available data and for a list of key references.

5. Treatment resistant schizophrenia & combined antipsychotics
Lack of convincing evidence (Yuzda 2000, Chong & Remington 2000)
Stahl (2002)
Only consider following lack of response to ‘multiple’ adequate trials of antipsychotic monotherapy
Close monitoring of a time-limited trial
Continuation only if evident therapeutic benefit
Miller et al 2004 (Texas Medication Algorithm Project)
Combined antipsychotics only after clozapine has been refused, or non-response to clozapine trials - both monotherapy and augmentation
Several good quality reviews of the efficacy and tolerability of combined antipsychotcs have been published. All conclude that there is a lack of convincing evidence to support this practice.
The data contained in these reviews led Stahl to reach his conclusions as outlined on the slide.
Note that it is not possible to say with certainty that combined antipsychotics are never justified. Highlight the point again that ‘no evidence of benefit’ is not the same as ‘evidence of no benefit’.
Treatment guidelines and clinical reviews all conclude that combined antipsychotics may be justified in some circumstances. Miller et al capture the spirit of the recommendation that is contained in good quality evidence based clinical guidelines.
Clozapine is the only antipsychotic that has been found to be effective in treatment-resistant schizophrenia. It makes good clinical sense that this evidence-based treatment should be tried alone, then in combination with a second antipsychotic drug (there is a small evidence base to support this) before combinations of antipsychotic drugs that do not include clozapine are prescribed.

6. Clozapine augmentation & combined antipsychotics
At least 30% of patients do not respond adequately to clozapine alone (Buckley et al 2001)
Combination of clozapine and conventional antipsychotic common in clinical practice.
Conventional antipsychotics added in 30-35% of cases in Denmark (McCarthy & Terkelsen 1995)
A second antipsychotic prescribed in 44% of hospital inpatients in the UK (Taylor et al, 2000).
US survey of 906 patients: 18% clozapine + antipsychotic (Buckley et al 2001)
Controlled data lacking but ‘safe and may be potentially efficacious when clozapine has produced less that optimal improvement’ (Chong & Remington 2000)
As noted by Buckley, not all patients will respond to treatment with clozapine.
Prescription surveys from various countries have consistently found that clozapine is used in combination with other antipsychotics in a minority of patients. This finding is consistent with the above.
There are currently a small number of RCTs of clozapine augmentation with a second antipsychotic in patients who have failed to respond to clozapine alone.
Data are conflicting and more studies are clearly required but while these are awaited, it seems reasonable to augment clozapine with a second antipsychotic drug in patients who have not responded to an adequate trial of clozapine monotherapy: arguably treatment for at least six months & evidence of an adequate serum level (? above 0.5mg/L) for at least 6 weeks.

7. The evidence base for high-dose antipsychotics
Doses in SPCs are the best balance between efficacy and side effects and should be used as standard practice (Royal College of Psychiatrists, 2006).
Controlled studies comparing very high doses of first-generation antipsychotics with standard dosage regimens for treatment resistant schizophrenia all failed to show a significant advantage for the high dosage (Thompson, 1994; Royal College of Psychiatrists, 2006).
Side effects are increased.
The summary of product characteristics (SPC) for a drug outlines the licensed dosage range for that drug. This dosage range has been determined from clinical trials as being associated with the best balance between efficacy and side effects. Doses below this range are too low to be effective in most patients and doses above this range are associated with a side effect profile that is considered to be unacceptable (usually in the context of no or minimal additional improvement in target symptoms).
The Royal College of Psychiatrists has reviewed the literature on the use of high dose (above SPC limits) antipsychotics and produced a consensus statement in 1994; the consensus was that there was no evidence to support high dose prescribing. This consensus statement was revisited in 2006 and all of the relevant literature published since 1994 was considered. The conclusion did not change.

8. Audit standards Audit standard 1
The total daily prescribed dose of antipsychotic drugs should be within SPC/BNF limits (Royal College of Psychiatrists, 2006).
Audit standard 2
Individuals receive only one antipsychotic at a time. This standard applies to 100% of individuals with schizophrenia. Exceptions: ‘Individuals with schizophrenia who are receiving clozapine but who have not responded sufficiently; and individuals who are changing from one antipsychotic to another’ (NICE schizophrenia guideline).
Audit standard 3
First (typical) and second generation (atypical) antipsychotic drugs are not prescribed concurrently. This standard applies to 100% of individuals with schizophrenia. Exceptions: ‘Any concurrent prescriptions are for a short period to cover changeover of medication. Local teams should agree on what constitutes a changeover period for audit purposes’ (NICE schizophrenia guideline).
Three standards are used in this audit.
The first is derived from the Royal College of Psychiatrists’ consensus statement on high dose antipsychotics, and the second and third from the NICE schizophrenia guideline.
POMH-UK recognises that NICE guidance/guidelines do not apply directly in Scotland (where guidelines are produced by SIGN). The contents of clinical guidelines produced by these 2 organisations rarely differ in any significant way.

9. Topic 1 quality-improvement audit cycle
A baseline audit against standards
Quality improvement change interventions that Trusts/clinical teams/individual clinicians may choose to participate in or not.
A re-audit after 12 months
Feedback and regional events
Further work… under development
The following slides report on the Topic 1d supplementary audit data conducted in Feb 2009
A baseline audit was conducted in January 2006.
Participating wards were offered a range of change interventions over the following 6 months before a re-audit was conducted in January 2007.
Participants have since received comprehensive reports benchmarking their practice against the standards and in comparison to the other participants. In July 2007 the POMH team ran feedback events for all participants at which findings and strategies were shared and teams.
The data presented in the following slides are from the 1d-supplementary audit conducted in February 2009.
Trust exec teams, Drugs & Therapeutics Committees, lead clinicians, clinical teams and individual clinicians are likely to be interested in some or all of this data.
Data for each individual Trust belongs to that Trust but the national dataset belongs to POMH-UK. Member Trusts are free to use the national dataset to stimulate discussion within the Trust.
National data should not be presented at external meetings without first seeking permission from POMH-UK.

10. Method Participating Trusts Self-selected Eligible patients
On acute adult or psychiatric intensive care ward
Prescribed one or more antipsychotic drugs
Data collected for each patient:
Basic demographic (age, gender, ethnicity).
Basic clinical (diagnosis, MHA status)
Prescription details (names & doses of antipsychotic drugs prescribed)
Clinical team’s reasons for prescribing combined antipsychotics.
Data collection
Collected on a single census day (in Jan 06 for the baseline audit and Jan 07 for the re-audit, Jan 08 for supplementary audit 1c and Feb 2009 for supplementary audit 1d) for each ward
Entered on-line & analysed using SPSS.
Note that the audit captured the antipsychotic drugs and doses that had been prescribed (what the patient could have received). This may differ from what was actually administered, particularly when PRN was involved.

11. Benchmarked audit report Slide presentation with speakers notes
Change interventions made available following baseline data collection
Benchmarked audit report
Slide presentation with speakers notes
Bringing about change workshop
Academic detailing workshop
Ready reckoner
Time-series chart
Educational workbook based on CBT principles
Reminder stickers for prescription charts
Educational poster
Between the baseline audit and 1-year re-audit every Trust received an audit report, benchmarking prescribing practice in each of their participating wards against each other and against the total Trust and national data. Data were also benchmarked at Trust level.
For further details of the other interventions listed, see the Topic 1 re-audit report.

12. National sample: dose & antipsychotic regimen at baseline and re-audit
Standard dose
High-dose
Total
Single
1815 (52%)
176
(5%)
1991 (57%)
1797
(55%)
187
(6%)
1984
(61%)
Combination no prn
159
148
(4%)
307
(9%)
186
145
331
(10%)
Combination with prn
253
(7%)
941
(27%)
1194 (34%)
168
788
(24%)
956
(29%)
2227 (64%)
1265 (36%)
3492 (100%)
2151
(66%)
1120
(34%)
3271
(100%)
Between baseline and re-audit, the proportion of patients prescribed a single antipsychotic increased from 58% to 60% and the proportion prescribed a regular dose (within BNF limits) increased from 64% to 66%.
These improvements in prescribing practice are very modest. The magnitude of change, at the national level, was not statistically significant.
As can be seen, the major contribution towards high dose prescribing was from PRN.

13. National sample: dose & antipsychotic regimen at supplementary audit 1d
Standard dose
High-dose
Total
Single
2549
(60%)
257
(6%)
2806
(66%)
Combination no prn
214
(5%)
185
(4%)
399
(9%)
Combination with prn
197
867
(20%)
1064
(25%)
2960
(69%)
1309
(31%)
4269
(100%)
The results show an increase in the proportion of patients in the TNS prescribed a single antipsychotic (58% of patients were prescribed a single antipsychotic at baseline, 60% at re-audit, 60% at supplementary audit 1c and 66% at supplementary audit 1d) and the proportion of patients prescribed a dose within BNF limits (64% of patients were prescribed a dose within BNF limits at baseline, 66% at re-audit, 62% at supplementary audit 1c and 69% at supplementary audit 1d). Note that it was not the same Trusts that participated at each time point.

14. National sample: combining FGA and SGA antipsychotics at supplementary audit 1d
Percentages shown on the histogram bars in Figure 1 refer to the proportion of the total national sample. Thirty-four percent were prescribed combined antipsychotics, and of these, 68% were prescribed a FGA in combination with a SGA. The results show a reduction in the proportion of patients prescribed a FGA in combination with a SGA (31% of patients were prescribed a FGA in combination with a SGA at baseline, 29% at re-audit, 30% at supplementary audit 1c and 23% at supplementary audit 1d)

15. Practice against the three audit standards at each stage of data collection
* Please note that the TNS has been split into two groups for the data collection period February 2009; those that had also participated in any or all of the previous audit stages of Topic 1 (baseline, re-audit or supplementary audit 1c) (n=2546) and those that had not (n=1723).
This Figure shows that prescribing practice with respect to high-dose and combined antipsychotics was relatively stable overall in the 2 years between the baseline and first supplementary audit, before moving closer to the standards in this second supplementary audit. Prescribing practice in Trusts that participated for the first time in this second supplementary audit, was closer to the audit standards overall than was found in the baseline audit, but for standards 2 and 3, performance was not as close as in those Trusts that had completed one or more previous audits. This suggests that; (1) the background prevalence of high-dose and combined antipsychotic prescribing may be falling, and that; (2) participation in one or more audit cycles may have an additional effect in moving prescribing closer to the standards. Such change takes time.

16. Proportion of patients prescribed a high dose at baseline and supplementary audit 1d
Proportion of patients prescribed a high dose of antipsychotic at baseline (January 2006, n=3429) and at supplementary follow-up audit 1d (February 2009, n=4269) for each trust that participated at both stages and the total national samples.
Of the 18 Trusts that took part in both the baseline (January 2006) and supplementary 1d (February 2009) audits, 11 showed a reduction in the proportion of patients prescribed a high dose over this time period. Overall the data show a significant reduction in the mean proportion of patients prescribed a high dose of antipsychotic at supplementary follow-up 1d compared to at baseline (t=2.108 (d.f.=17), p=0.05).

17. Data collection period
Avoid high-dose and combined antipsychotics
Table 3: Proportion of patients in each Trust and the total national sample receiving a high dose of antipsychotic, a combination of antipsychotics, and specifically FGA and SGA antipsychotics concurrently, at each stage of the audit process.
Trusts (by code)
Audit standard
Data collection period
January 2006
January 2007
January 2008
February 2009 40
High dose
45%
51% -
Combination
60%
48%
FGA and SGA
33%
40%
TNS
36%
34%
38%
31%
42%
29%
30%
23%

18. Trust level comparison: regular or high-dose at 1d
The numbers on the histogram represent actual numbers of patients (the height of each bar represents the percentage)
The Trust at the left side of the Figure had the highest proportion of patients prescribed antipsychotic doses within BNF limits, and the Trust at the right side of the Figure the least. The proportion for the total national sample is shown at the extreme right of the Figure. Combined antipsychotics were the major cause of high-dose prescribing (see also Table 1).
Trusts that previously participated in Topic 1 baseline, re-audit and supplementary audit 1c are marked ***
Trusts that previously participated in Topic 1 baseline and re-audit only are marked **
Trusts that previously participated in Topic 1 supplementary audit 1c only are marked *

19. Trust level comparison: single antipsychotic, regular or high-dose
The numbers on the histogram represent actual numbers of patients (the height of each bar represents the percentage)
The Trust on the left side of Figure 3 had the highest proportion of patients prescribed a single antipsychotic and the Trust on the right side the least. The characteristics of the total national sample are shown at the extreme right of the Figure. Only a small proportion of patients were prescribed a high-dose of a single antipsychotic drug.
Trusts that previously participated in Topic 1 baseline, re-audit and supplementary audit 1c are marked ***
Trusts that previously participated in Topic 1 baseline and re-audit only are marked **
Trusts that previously participated in Topic 1 supplementary audit 1c only are marked *

20. Trust level comparison: combining FGA & SGA antipsychotics
The numbers on the histogram represent actual numbers of patients receiving a combination of both FGA and SGA antipsychotic (the height of each bar represents the percentage).
Trust 25 (left side of the Figure) had the greatest proportion of patients prescribed a single antipsychotic (either FGA or SGA) and Trust 80 (right side of the Figure), the lowest. The characteristics of the total national sample are shown at the extreme right of the Figure.

21. Ward level comparison: high-dose and combined antipsychotics
The numbers on the histogram represent actual numbers of patients (the height of each bar represents the percentage)
For your Trust, prescribing practice in the ward at the left side of the Figure is closest to the audit standards. Practice in your Trust as a whole and in the total national sample can be seen at the far right of the Figure.

22. Ward level comparison: contribution of prn to combination prescriptions
The numbers on the histogram represent actual numbers of patients (the height of each bar represents the percentage)
This figure identifies the number of patients in each ward in your Trust who were prescribed a single antipsychotic, two or more regular antipsychotics only (no PRN) and those who received antipsychotic combinations that included PRN. For your Trust, prescribing practice in the ward at the left side of the Figure is closest to the audit standards. Practice in the ward at the right of the Figure is furthest from the standards. Practice in your Trust as a whole and in the total national sample can be seen at the far right of the Figure.

23. Summary
Audit standard 1: The dose of an individual antipsychotic should be within its SPC/BNF limits.
36% of patients were prescribed a high dose at baseline, 34% at re-audit, 38% at supplementary audit 1c and 31% at supplementary audit 1d .
Audit standard 2: Individuals receive only one antipsychotic at a time.
42% were prescribed combined antipsychotics at baseline, 40% at re-audit, 40% at 1c and 34% at 1d.
On all occasions the major cause of combined antipsychotics was PRN.
Audit standard 3: First and second generation antipsychotic drugs are not prescribed concurrently.
31% were prescribed a FGA & SGA concurrently at baseline, 29% at re-audit, 30% at 1c and 23% at 1d.
The major cause of high-dose is combined antipsychotics and the majority of prescriptions for combined antipsychotics include PRN. The national level data suggest that prescribing practice was relatively consistent over the two year period between the baseline and first supplementary audit, before moving towards the standards in this second supplementary audit. However, the majority of Trusts that participated in all three stages of data collection up to the first supplementary audit showed improvement against the audit standards over this time period. Further, of the 18 Trusts that participated at baseline, re-audit and this second supplementary audit, 10 showed improvements in performance against all three audit standards. The prescribing practice in Trusts that participated for the first time in this second supplementary audit was closer overall to the audit standards than was found in the baseline audit, but for standards 2 and 3, performance was not as close as in those Trusts that had completed one or more previous audits. This suggests that; (1) the background prevalence of high-dose and combined antipsychotic prescribing may be falling, and that; (2) participation in one or more audit cycles may have an additional effect in moving prescribing closer to the standards. Such change takes time.